Thiopurine Methyltransferase Research Articles

The Evolving Role of Thiopurines in Inflammatory Bowel Disease.

With the advent of biologic therapies for the treatment of inflammatory bowel disease, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions and post-surgical maintenance of remission and as combination therapies to reduce immunogenicities of biologic agents. Due to pharmacogenetics of thiopurine S-methyltransferase, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, and dermatologic evaluations and protection from sun exposure. Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.

Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics.

Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.

Variations in Insurance Policies Regarding Adherence to the AGA Guideline for Therapeutic Drug Monitoring in IBD.

The American Gastroenterological Association (AGA) published guidelines on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) in August 2017 recommending use of reactive TDM to guide treatment changes in patients with active IBD who are being treated with anti-tumor necrosis factor (anti-TNF) agents or thiopurines. We sought to determine if changes in national clinical practice guidelines result in changes in health care insurance policies within 6 months of publication. Using the National Association of Insurance Commissioners Market Share Reports of the top 125 insurance companies by market share in 2016, we reviewed the largest 50 companies for their publicly available online policies regarding TDM of anti-TNF and thiopurine in IBD. For those with available policies, we looked for whether proactive and/or reactive TDM was covered. Policies were also looked for genetic or enzymatic activity of thiopurine methyltransferase (TPMT) testing before use of thiopurine. All these policies were reviewed within the week of publication of the AGA guideline. They were reviewed again 1, 3, and 6 months later for evaluation of any policy changes after the published AGA guidelines. Fifty of the largest insurance company policies were included. With regards to TDM policy for anti-TNF, we did not find a difference between baseline and 6 months values (P=0.38). With regards to TDM policy for thiopurine, we did not find a difference between baseline and 6 months values (P=1.00). About half of the companies did not have a policy regarding TPMT testing for thiopurine use. Of those with available policies for TPMT testing, there was no difference between baseline and 6 months values (P=0.13). Even after publication of national guidelines, a large number of the largest health insurance companies do not have a policy regarding reactive TDM for anti-TNF and/or thiopurines. Majority of those with a policy, fail to meet the current standards set forth by the practice guidelines. A significant gap remains between the insurance policies and AGA guidelines. Further studies are needed to determine how to effectuate change to improve insurance company adherence to clinical practice guidelines.

Thiopurine Methyltransferase Genetic Polymorphisms and Activity and Metabolic Products of Azathioprine in Patients with Inflammatory Bowel Disease.

Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. There is a correlation between thiopurine drug metabolism, response, and toxicity and genetic polymorphism of TPMT. The aim of this study is to assess TPMT genetic polymorphisms activity and metabolic products of AZA in patients with IBD. Blood samples were obtained from 50 IBD unrelated patients from a private laboratory. We used polymerase chain reaction-restriction length polymorphism (PCR-RFLP) and allele-specific PCRbased assays to determine the TPMT gene for the different variants. A high-performance liquid chromatography system (HPLC) was carried out to determine the whole blood 6-TGN concentration. Determination of serum TMPT activity was done by ELISA kit. In IBD patients, 46/50 (92%) subjects were homozygous for the wild-type allele (TPMT*1/*1). Mutant TPMT*1/*2 and TPMT*1/*3C alleles were found in 4/46 (8%) and 3/47 (6%) of IBD patients, respectively. TPMT*1/*3B variant was not detected in any of the IBD patients. TPMT enzyme activity was higher in wild-type than that mutant variants TPMT*1/*2 and TPMT*1/*3C, suggesting that there are statistically significant differences between 6-TG levels and polymorphisms of TMPT enzyme. 6-TG levels significantly increased in IBD patients mutant variants TPMT*1/*2 and TPMT*1/*3C. Our results showed that TPMT polymorphisms are associated with 6-TGN levels in patients using AZA. This study suggests that AZA dosage may be determined according to the high or low prevalence of a TPMT genotype. Moreover, the results present the determination of metabolite for assessing possible safe effective dosage of the drug.

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients.

Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15. GVBNUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15-and-TPMT combined interaction analyses, GVBNUDT15 , TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.

PB1658 RELEVANCE OF TPMT, NUDT15 AND ABCC4 GENOTYPING IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA

Background:Acute lymphoblastic leukemia/lymphoma (ALL/lymphoma) is the most common pediatric cancer. The approved standard treatment includes a 24‐month maintenance phase with 6‐mercaptopurine (6‐MP) and methotrexate, achieving complete responses in 80% of the cases.According to the literature, there are genetic polymorphisms in enzymes involved in the thiopurine drugs metabolism (namely, thiopurine methyltransferase or TPMT and nudix hydrolase 15 or NUDT15) and transport (ATP binding cassette subfamily C member or ABCC4) that can influence their therapeutic effect and cause adverse events along this phase (myelosuppression, hepatotoxicity, pancreatitis, among others).Inherited TPMT deficiency (mainly, variants 2, 3A, 3B and 3C) is the primary genetic cause of thiopurine intolerance in Europeans and Africans, whereas risk alleles in NUDT15 explain most of thiopurine‐related myelosuppression in Asians and Hispanics. Not so well established are the presence of genetic variants in genes coding for drug transport proteins like ABCC4.The Clinical Pharmacogenetics Implementation Consortium has published recommendations for adjusting starting doses based on TPMT/NUDT15 genotypes but, although relevant to prevent severe adverse effects, these studies are not yet universally implemented.Aims:Genotyping pediatric ALL/lymphoma with hematologic toxicity along the maintenance phase of the oncologic treatment.Methods:Patients diagnosed with ALL/lymphoma since 2012, presenting hematologic toxicity to 6‐MP and requiring regular dose adjustments along the maintenance phase were studied for TPMT genotype. In case of negative study for TPMT, NUDT15 and ABCC4 genotypes were also explored.Results:Eleven patients were identified, median age 8 [1‐14] years, male gender in 6 cases (54.5%). Seven patients had a B‐ALL (63.6%), one had a T‐ALL and three had a lymphoma.Six patients already finished their maintenance phase. These had a median of 19.5 [7‐35] adjustments for 6‐MP dose along this phase for hematologic toxicity, with a median time of 14 days between adjustments. One of these patients was identified with the genotype TPMT 3A∗ (the most common variant allele in the Caucasian population that confers low enzyme activity), and required 23 adjustments for hematologic toxicity in a median time of 14 days [3‐116] until reaching the adequate dose.Five patients are still in the maintenance phase (median time of 9 [2‐11] months) and had already a median of 10 [2‐20] adjustments for hematologic toxicity, in a median time of 14 days between adjustments. From these, there are 3 cases identified with an ABCC4 genotype that seem to predispose to adverse hematologic events, requiring closer medical monitoring.All these 11 patients are alive and have no oncologic disease. Overall survival is 2 [1‐7] years and progression free survival is also 2 [1‐4] years.Summary/Conclusion:This study led to the implementation of TPMT genotyping in all Pediatric ALL/lymphoma patients in our center, before the maintenance phase and to a 50% dose reduction of 6‐MP in those with TPMT forms with low activity (TPMT∗2, TPMT∗3B, TPMT∗3C and TPMT∗3A) to reduce hematologic toxicity related to an excessive dose administered. Based on the results obtained for ABCC4 and NUDT15 genotypes and according to the literature, it is still not recommended the study of these additional genes for all patients.

Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden

Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient’s TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis.

The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase (TPMT) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT∗3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg−1 ⋅ d−1 and 0.96 (0.83, 1.19) mg ⋅ kg−1 ⋅ d−1, respectively (P = 0.028). In contrast, no significant association was observed for TPMT∗3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg−1 ⋅ d−1. Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.

Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis.

Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known. Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine. A decision tree was built to compare the conventional weight-based dosing strategy with phenotyping and with genotyping using a micro-simulation model of patients with inflammatory bowel disease from the perspective of the French health care system. The time horizon was set up as 1year. Only direct medical costs were used. Data used were obtained from previous reports, except for screening test and admission costs, which were from real cases. The main outcome was the cost-effectiveness ratios, with an effectiveness criterion of one averted severe myelotoxicity episode. The total expected cost of the no screening strategy was €409/patient, the total expected cost of the phenotyping strategy was €427/patient, and the total expected cost of the genotyping strategy was €476/patient. The incremental cost-effectiveness ratio was €2602/severe myelotoxicity averted in using the phenotyping strategy, and €11,244/severe myelotoxicity averted in the genotyping strategy compared to the no screening strategy. At prevalence rates of severe myelotoxicity > 1%, phenotyping dominated genotyping and conventional strategies. The phenotype-based strategy to screen for TPMT deficiency dominates (cheaper and more effective) the genotype-based screening strategy in France. Phenotype-based screening dominates no screening in populations with a prevalence of severe myelosuppression due to azathioprine of > 1%.

Development of duplex-crossed allele-specific PCR targeting of TPMT*3B and *3C using crossed allele-specific blockers to eliminate non-specific amplification

Prospective testing for variants in the thiopurine S-methyltransferase (TPMT) is considered a key process in the development of thiopurine therapy. This testing is done to avoid toxicity and side effects in the management of diverse immunological and malignant conditions. Real-time fluorescent PCR techniques using duplex-crossed allele-specific primers in a single tube (DCAS-PCR) were developed in this study to genotype the common loss-of-function TPMT*3B c.460G > A (rs1800460) and TPMT*3C c.719A > G (rs1142345) usually occurring in individuals of Chinese ethnicity. In this method, several integrated strategies were used to completely eliminate the non-specific amplification that is commonly presented in traditional allele-specific (AS) PCR. These strategies include using AS-primers (ASP) that both are artificially mismatched in the penultimate positions and phosphorothioate modifications in the 5′-termini positions. In the assay, an AS-blocker was used, locus-specific TaqMan (LST) probes were used and we used at least two fragments were simultaneously amplified in a single tube which satisfy the thermodynamic characteristics of DNA polymerase to eliminate non-specific amplification. In a group of 200 unselected subjects, the results showed that 8 samples were heterozygous of TPMT*3C, and all samples possessed wild-type TPMT*3B. There was no non-specific amplification, and the genotypes were 100% consistent with Sanger sequencing.

Development and validation of a UPLC-UV method for the quantification of thiopurine methyltransferase enzyme activity in human erythrocytes

Thiopurines are drugs widely used for the treatment of autoimmune conditions, inflammatory bowel disease or acute lymphoblastic leukemia. Determination of thiopurine methyltransferase activity (TPMT), a major determinant of thiopurines toxicity, has been suggested before implementing thiopurine treatment. An ultraperformance liquid chromatography (UPLC) method was developed and validated for the quantification of TPMT enzyme activity based on the conversion of 6-mercaptopurine (6-MP) to 6-methylmercaptopurine (6-MMP) using S-adenosyl-L-methionine (SAM) as methyl donor in red blood cell lysates (RBC). This method was improved from a previous laborious high performance liquid chromatography (HPLC) method, using a lower volume of injection and with a shorter runtime.After incubation and protein precipitation 6-MMP was separated on a HSS-T3 (2.1 × 50 mm, 1.8 μm) column and monitored by UV detection (290 nm). A change on the organic solvent used to dissolve 6-MP resulted in a reduction of interference by endogenous or non-enzymatic methylated 6-MMP. A full validation of the 6-MMP assay was performed according to the FDA and EMA guidelines. The method was linear from 0.125 to 2 nmol/mL, with acceptable values of accuracy and precision.The method was applied in 106 patients treated with thiopurines whose TPMT activity was previously quantified by HPLC. Evaluation through Bland-Altman plot showed that TPMT activities were in agreement between both methods.

Combined evaluation of genotype and phenotype of thiopurine S-methyltransferase (TPMT) in the clinical management of patients in chronic therapy with azathioprine.

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.

Retrospective Data Analysis of the Influence of Age and Sex on TPMT Activity and Its Phenotype-Genotype Correlation.

Therapeutic efficacy and toxicity of thiopurine drugs (used as anticancer and immunosuppressant agents) are affected by thiopurine S-methyltransferase (TPMT) enzyme activity. TPMT genotype and/or phenotype is used to predict the risk for adverse effects before drug administration. Inosine triphosphate pyrophosphatase (ITPA) is another enzyme involved in thiopurine metabolism. In this study, we aimed to evaluate (a) frequency of various TPMT phenotypes and genotypes, (b) correlations between them, (c) influence of age and sex on TPMT activity, and (d) distribution of ITPA variants among various TPMT subgroups. TPMT enzyme activity was determined by LC-MS/MS. TPMT (*2,*3A-C) and ITPA (rs1127354, rs7270101) genotypes were determined using a customized TaqMan® OpenArray®. TPMT enzyme activity varied largely (6.3-90 U/mL). The frequency of low, intermediate, normal, and high activity was 0.5% (n = 230), 13.1% (n = 5998), 86.1% (n = 39448), and 0.28% (n = 126), respectively. No significant difference in TPMT activity in relation to age and sex was found. Genotype analysis revealed the frequency of variant TPMT alleles was 6.73% (*3A, n = 344), 0.05% (*3B, n = 2), 2.22% (*3C, n = 95), and 0.42% (*2, n = 19). Analysis of paired phenotype and genotype showed that TPMT activity in samples with variant allele(s) was significantly lower than those without variant alleles. Lastly, an equal distribution of ITPA variants was found among normal and abnormal TPMT activity. This retrospective data analysis demonstrated a clustering of variant TPMT genotypes with phenotypes, no significant influence of age and sex on TPMT activity, and an equal distribution of ITPA variants among various TPMT subgroups.

Frequency of serious adverse events of thiopurine treatment in normal thiopurine S-methyltransferase genotype children with inflammatory bowel disease

Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases. To evaluate the frequency of severe side effects, such as myelosuppression and hepatotoxicity, at standard or decreased azathioprine doses in children with inflammatory bowel disease who do not exhibit any of the four most common variant alleles. Retrospective analysis of children with inflammatory bowel disease treated with azathioprine at a single tertiary referral center. 51 patients were identified (44: Crohn's disease, 7: ulcerative colitis; male ratio: 28/51; mean age at diagnosis: 12.4 years). Two patients discontinued azathioprine arbitrarily whereas in one patient it was stopped due to serious pancreatitis and in another one because of severe flu-like symptoms. None of the remaining 47 patients exhibited hepatotoxicity suggesting abnormally high thiopurine S-methyltransferase activity. Four patients (8.5%) had profound myelosuppression on less than 1 mg/kg/day azathioprine requiring discontinuation of the drug, and all of them showed complete bone marrow recovery subsequently. No myelosuppression occurred in the remaining 43 patients on 2.17 ± 0.31 mg/kg/day (mean ± SD) azathioprine treatment. Regular blood tests are necessary on thiopurine therapy despite normal thiopurine S-methyltransferase genotype because of the risk of myelosuppression. The four most common variant alleles were identified in routine genotyping only, therefore most likely rare variant allele(s) or polymorphism of other enzymes involved in thiopurine metabolism account for the aforementioned four cases with profound bone marrow suppression. Thiopurine metabolite monitoring is the key for individualized treatment when optimal dosing can be achieved with the least side effects. Orv Hetil. 2019; 160(5): 179-185.

Genotype-Guided Thiopurine Dosing Does not Lead to Additional Costs in Patients With Inflammatory Bowel Disease.

Background and AimsDecreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life.MethodsAn a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications.ResultsThe intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were €52 per patient [95% percentiles −682, 569]. Mean incremental QALYs were 0.001 [95% percentiles −0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss.ConclusionsGenotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.

Systematic Review: Cost-effective Strategies of Optimizing Anti-tumor Necrosis and Immunomodulators in Inflammatory Bowel Disease

Medication costs in inflammatory bowel disease (IBD) are now the principal driver of health care costs. Cost-effective strategies to optimize and rationalize treatment are therefore necessary. A systematic review until April 30, 2018, was performed to identify economic evaluations of strategies to optimize infliximab, adalimumab, and immunomodulators for the treatment of IBD in adults. A qualitative synthesis of the identified studies was performed. Seventy articles were identified that met the inclusion criteria. Adalimumab seems cost-effective compared with infliximab as maintenance therapy for moderate to severe Crohn's disease (CD). Infusion costs are a significant additional treatment cost with infliximab. However, other studies found biosimilar infliximab more cost-effective than alternative biologics in fistulizing and moderate-severe luminal CD-although the latter did not reach a willingness-to-pay threshold of <$50,000. In moderate-severe ulcerative colitis, infliximab seems more cost-effective than adalimumab. Multiple tailored approaches to treatment based on objective markers of disease activity or efficacy have been shown to be cost-effective in CD, including following secondary loss of response to anti-TNF therapy for postoperative recurrence and in escalating treatment. For immunomodulator treatment, both thiopurine methyltransferase (TPMT) testing before commencing thiopurines and thiopurine metabolite testing for dose optimization seem cost-effective. In a win-win for patients and payers, several potential avenues to achieve cost-effectiveness-but also therapeutic optimization of anti-TNF therapies-were elucidated in this review with comparatively sparse data for immunomodulators. Optimizing immunomodulator and anti-tumor necrosis factor alpha therapy to achieve objective disease control seems to be cost-effective at conventional willingness-to-pay thresholds in a number of clinical settings.

P826 Unexplained higher frequency of mutant thiopurine S-methyltransferase genotypes in inflammatory bowel disease patients of Latvia population

P826 Unexplained higher frequency of mutant thiopurine S-methyltransferase genotypes in inflammatory bowel disease patients of Latvia population

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update.

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).

Alopecia as the first manifestation of azathioprine myelosuppression in a genetically predisposed patient

Azathioprine, an analog of mercaptopurine, is used for various inflammatory/autoimmune diseases in diverse fields such as rheumatology, ophthalmology, gastroenterology, and neurology. One of the dreaded side effects of this drug is myelosuppression, which can be either dose related or “idiosyncratic.” The latter group often manifests with sudden cytopenias and is often secondary to a genetic predisposition. Mutations in the genes thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) have been identified to predispose to severe myelosuppression with azathioprine. An important clinical clue that can precede the onset of myelosuppression is alopecia. Here, we describe the case of a young lady treated with azathioprine, who developed alopecia (progressing to alopecia totalis), which was followed by severe cytopenia – both of which recovered on stopping the drug. On genetic analysis, she was found to be homozygous for mutation in NUDT15 (C415T) but was negative for mutation in TPMT. We review various other cases reporting alopecia as a marker of azathioprine-induced myelosuppression and the genetic mutations described.

Germline variants in cancer therapy.

Cancer pharmacogenetics implies a complex combination of germline variants from the patient and somatic mutations in tumor cells. Somatic mutations meanwhile have become drugable targets or biomarkers, whereas germline mutations potentially predict adverse drug effects or drug response. Here, we evaluate hereditary variants in biotransforming enzymes and drug transporters, such as thiopurine S-methyltransferase, UDP-glucuronosyltransferase (UGT1A1), dihydropyrimidine dehydrogenase (DPD), as well as ABC transporters (ABCB1, ABCG2 and ABCC subfamily) with respect to cytostatics and targeted therapies. Furthermore, gene expression regulation with regards to epigenetics and posttranscriptional modification are discussed.